Killer Immunity and HIV Reservoirs

By Jeffrey Laurence, M.D., and Rowena Johnston, Ph.D.

Published Wednesday, February 12, 2014

Dr. Mathias LichterfeldIn seeking to define novel methods of eradicating persistently HIV-infected CD4+ T cells, many of our grantees have focused on pharmacological approaches such as drug treatments to target infected memory T cells. amfAR grantee Dr. Mathias Lichterfeld, writing in the January issue of the Journal of Acquired Immune Deficiency Syndromes, takes an immunological approach by focusing on the immune responses of “elite controllers,” people infected with HIV but capable of maintaining low viral loads and high T cell counts without the aid of antiretroviral therapy.

Dr. Lichterfeld, working at Harvard University and Massachusetts General Hospital, along with colleagues there and at China Medical University in Shenyang, focused on a major player in the T cell immune system: the CD8+ cytotoxic cell. These “killer T cells” are capable of destroying cells infected with viruses. The strength of this activity can be assessed by test-tube measures using a patient’s blood. The research team found that the CD8+ T cells’ ability to kill HIV-infected cells was significantly greater in elite controllers than in patients requiring antiretroviral therapy to suppress virus. Of even greater interest was that the elite controllers had a corresponding reduced latent viral reservoir size.

Further studies showed a consistent relationship among a genetic marker called MHC-1 B57, high killer T cell activity, and low virus reservoir. In addition, the effect was most pronounced in naïve T cells—a type of immune cell that constitutes the reservoir but has been less of a focus for researchers than the memory T cell compartment.

Future experiments should help define why HIV-infected CD4+ T cells from elite controllers are more susceptible to CD8-mediated killing. They should also reveal whether, in some instances, this can be a double-edged sword—contributing to lowering latent reservoirs but then not shutting off, leading to a higher risk for CD4 cell loss when the virus itself appears greatly suppressed.

Efforts to cure HIV will need methods of killing persistently infected cells. Dr. Lichterfeld and colleagues will add to our knowledge of how this might be achieved by CD8+ T cells if those cells’ responses can be fine-tuned and directed toward infected cells.

Dr. Laurence is amfAR’s senior scientific consultant.Dr. Johnston is amfAR’s vice president and director of research.